(Applicant's Abstract) The long-term objective of this SCOR is to further our understanding of the pathogenesis of the idiopathic interstitial pneumonias (UP). A clear understanding of the pathogenesis of these diseases is required to develop new treatment strategies. The central hypothesis for this SCOR proposal is: Local alterations in the elaboration of effector molecules or in the expression of receptors by inflammatory, epithelial, and mesenchymal cells create an alveolar microenvironment that favors the fibroproliferative response rather than normal repair. Such dysregulation in autocrine and/or paracrine regulatory loops determine susceptibility to and expression of fibrotic lung disease. In each project of this SCOR, this central hypothesis will be extended to define the role of a specific set of mediators and/or receptors in pathobiological processes relevant to fibrogenesis. These mediators include cytokines, chemokines, elcosanoids and proteases. Studies will utilize animal models of fibrosis and/or patients with HP to examine abnormalities in cells and tissues and the role of each mediator in the pathobiology of fibrosis. An important feature is the mechanistic insights these studies provide to the use of standard (prednisone, azathioprine + prednisone) and novel (5-lipoxygenase inhibitor, zileuton) therapeutic agents under investigation in our ongoing clinical project. This SCOR will take a multi-disciplinary approach to testing these hypotheses. The expertise of investigators trained in Internal Medicine, Pathology, Cell and Molecular Biology, Biochemistry, and Biostatistics will be utilized. The strength of this proposal are the investigators long-standing interests in fibrotic lung disease, a proven commitment to collaborative research by both clinicians and basic scientists, access to a large population of IIP patients, and extraordinary institutional resources of biomedical Research. This SCOR capitalizes on a bench to bedside continuum of research that is crucial to translate advances in basic research to the clinical arena.